Targeting Microvascular Contributors to Impaired Functional Exercise Capacity in Diabetes

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Diabetes (DM) shortens lifespan, an impact that is not fully explained by traditional cardiovascular (CV) risk factors. Functional Exercise Capacity (FEC) is a universal predictor of CV and all-cause mortality and it is decreased in people with diabetes. The overall goal of our combined basic and clinical research program is to understand and treat impaired FEC in DM to prevent premature mortality. New data from our lab indicate that: Oxygen delivery uniquely limits in vivo muscle mitochondrial function in DM (human); Modeling of muscle blood flow distribution reveals that the contributions of reduced flow and capillary density were minor relative to the contributions of heterogeneous flow distribution (rodent) ; Targeting of nitric oxide synthase/nitric oxide (NOS/NO) or glucagon like peptide 1 (GLP-1) impacts FEC (running distance) and demonstrate a correlation between muscle perfusion (blood flow, capillary density and blood flow distribution) and oxygen consumption. Hypothesis: Microvascular perfusion heterogeneity contributes to diabetes mediated muscle fatigue, decreased muscle VO2 and impaired FEC and these endpoints will improve with two different agents that improve muscle blood flow distribution -GLP-1 or Nitrites. SA#1: To test the hypothesis that will GLP-1 and Nitrites will prevent or restore hyperglycemia- mediated muscle perfusion heterogeneity, muscle fatigue and decreased muscle VO2: This aim will employ a mouse model with inducible hyperglycemia to examine the impact of hyperglycemia on muscle perfusion, muscle fatigue and muscle VO2. The second set of experiments will test the ability of GLP-1 or Nitrites, targeting eNOS/NO by different mechanisms, to prevent or restore these endpoints. SA#2: To examine the ability of GLP-1 or Nitrites to improve DM FEC and to augment the impact of exercise training: We will determine the impact of GLP-1 or Nitrites on exercise performance with and without hyperglycemia and exercise training. These experiments will address the overall hypothesis by exploring the impact of GLP-1 or Nitrites on FEC and the exercise training response. SA#3: To define the importance of GLP-1 receptors for muscle perfusion heterogeneity and function and for the adaptation to exercise training: Published and preliminary data indicate that GLP-1 can augment adaptation to exercise training and pilot data demonstrate that the GLP-1 receptor antagonist interferes with the adaptive exercise training response. These studies will clarify whether endothelial cell GLP-1 receptors are required for cardiometabolic adaptation to exercise training. Impact of these studies on the Veteran Population: Diabetes decreases life expectancy and is highly prevalent in Veterans. Successful execution of this research program will provide critical preclinical data for interventions that may acutely improve function and increase the impact of physical activity on cardiovascular health in people with diabetes.